The primary problem associated with topical applications of drugs to the eye is that the human eye is a very sensitive organ and any substance which is not compatible with it causes irritation and pain. This evokes blinking and reflex-tearing, which is a physiological reaction intended for removal of the irritating substance from the ocular surface. Irritation is a major cause of poor patient compliance with many ophthalmic drugs. This phenomenon is aggravated by the need to include relatively high concentrations of a drug in such ophthalmic compositions in order to obtain a therapeutic effect, since bioavailability of topically applied ophthalmic drugs is generally very poor. Thus, there is no doubt that a reduction in the irritating effect of a drug will enable increased ocular drug bioavailability, increased patient compliance with the drug, and enhanced therapeutic efficacy of the drug.
Currently, aqueous solutions are by far the most common vehicles for ophthalmic drugs. Such vehicles have a serious drawback, however, in that the ocular bioavailability of drugs administered thereby is generally very poor due to rapid drainage and tear turnover. See Fitzgerald et al. (1987) J. Pharm. Pharmacol. 39:487-490. A typical dose of ophthalmic solution is in the range of about 50-100 .mu.l, which far exceeds the normal lachrymal volume of about 7-10 .mu.l. Thus, the portion of the dose that is not eliminated by spillage from the pulberal fissure is quickly drained. Furthermore, lachrymation and physiological tear turnover, which in humans is about 16% per minute under normal conditions, increases after the introduction of the solution, resulting in rapid dilution of the remaining amount of drug that has not been spilled or drained. As a consequence, the contact time with the absorbing surfaces of the eye (i.e., the cornea and sclera) of drugs which are applied to the eye via liquid aqueous compositions is less than about two minutes.
Another drawback of aqueous vehicles is that many drugs which may potentially be used in eye therapy are hydrophobic and their delivery into the eye by such aqueous vehicles is not possible. While such hydrophobic drugs may potentially be administered to the eye in conjunction with various organic solvents, the use of such solvents usually causes irritation and inflammatory reactions. See Harmia et al. (1987) Pharm. Acta Helv. 62:322-332.
Attempts have been made to develop various delivery vehicles in which the drug residence time in the eye is increased. The most direct approach for achieving this goal is by an increase in the viscosity of the vehicle. Thus, various viscous vehicles, such as hydrogels or ointments, have been attempted, some of which also enable delivery of hydrophobic drugs into the eye. Additionally, many attempts to use various non-conventional carriers, such as liposomes, micellar solutions and nanoparticles, as vehicles of ophthalmic drugs have also been made. While the use of such delivery systems may provide limited success in prolonging the residence time of drugs in the eye and hence some enhancement of the ocular bio-availability, such carriers also produce various deleterious side effects. See Harmia et al., supra., Saettone et al. (1988) J. Pharm. 43:67-70 and Meisner et al. (1989) Int. J. Pharm. 55:105-113.
Emulsions have also been suggested as vehicles for delivery of drugs to the eye in references such as EP 391,369, Ellis et al. (1987) J. Ocular Pharmcol. (U.S.) 3:121-128, and Shell (1984) Surv. Ophthalmol. 29:177-178. Nevertheless, the practical inability to realize the potential of emulsion systems for ocular drug delivery stems predominantly from two problems. First, ocular drug formulations must be comfortable to the patient as well as safe, due to the sensitivity of the delicate eye tissues involved. Second, emulsions are generally metastable dispersions of immiscible fluids and these instability problems must be overcome.
An emulsion is a dispersion of oil in water ("o/w"), and can be defined as either a macroemulsion or a microemulsion. A macroemulsion is a cloudy turbid composition having an oil-droplet size of 0.5 to 100 .mu.m and is generally thermodynamically unstable. In comparison, a microemulsion is a translucent to transparent composition having a droplet size of 0.005 to 0.5 .mu.m, is thermodynamically stable and is generally self emulsifying. See, e.g., Friberg et al. (1987) Microemulsions Structure and Dynamics, CRC Press Inc., Boca Raton, Fla., pp. 154. Also, the proportion of surfactants to oil required to generate microemulsions is generally much higher than in macroemulsions.
Emulsions developed specifically for ophthalmic use have attempted to solve the problem of inherent instability through the use of microemulsions or the addition of stabilizing polymers to classical emulsions. In several instances, specific drugs have been formulated successfully in microemulsions. Examples of this approach include ophthalmic microemulsions of tepoxalin, as disclosed in EP 480,690, or flurbiprofen, as disclosed in EP 253,472.
An alternative approach to solve the problem of emulsion instability utilizes lightly crosslinked polymers, as exemplified by the autoclavable emulsions for ophthalmic use which are disclosed in EP 028,110.
In addition, the use of emulsions in ophthalmic preparations has been limited to a large extent by the inclusion of surfactants in the emulsions which surfactants are highly irritating to the eye. For example, the use of the emulsion preparations of EP 391,369 are limited considerably by the irritating effect of the ionic surfactants which are used in those emulsions. Thus, to date no commercially successful ophthalmic compositions in the form of oil-in-water emulsions are available.
The present invention solves the problem of emulsion instability without resorting to either of the prior art suggestions by instead converting classical emulsions to submicron emulsions with the input of energy by shear forces and homogenization to provide submicron emulsions possessing substantially reduced eye irritation properties. Also, the irritation of the eye is further reduced through the use of non-irritating non-ionic surfactants in such emulsions. Thus, when drugs are included with these submicron emulsions, the present invention provides ophthalmic compositions which are improved over those which are currently available in the art. In accordance with the present invention, effective means for reducing irritation of the eye, particularly such irritation which is drug-induced, is provided for the first time and thereby a long felt need has been fulfilled.